4-Aryl-4-piperidinecarbinols

ABSTRACT

4-Aryl-4-piperidinecarbinols, for example, ##STR1## useful as antidepressants and, in some cases, as anorectic agents.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of patent application Ser. No. 376,229filed May 7, 1982, now abandoned.

DESCRIPTION TECHNICAL FIELD

This invention relates to 4-aryl-4-piperidinecarbinols which are usefulas antidepressants and, in some cases, an anorectic agents.

BACKGROUND

Mental illness encompasses both psychoses and neuroses. Symptomsrequiring treatment include depression, anxiety, agitation, andhallucinations. Among the drugs used particularly for treatment of bothreactive and endogenous depressions are monoamine oxidase (MAO)inhibitors, such as iproniazide, tranylcypromine, nialamide, phenelzine,and pargyline, and the non-MAO-inhibiting tricyclic aromaticdibenzazepines, such as imipramine, and dibenzocycloheptanes such asamitriptyline.

All of these drugs have adverse side effects that limit theirusefulness. MAO inhibitors may benefit milder forms of depression, butthe risk of serious toxic effects is a strong argument against theiruse. They may cause liver damage and acute hypertension, especially ifgiven in conjunction with cheese, bananas, or other amine-containingfoods. The MAO inhibitors may also cause tremors, insomnia,hyperhydrosis, agitation, hypermanic behaviour, confusion,hallucinations, convulsions and orthostatic hypotension. They frequentlycause dizziness, vertigo, headache, inhibition of ejaculation,difficulty in urination, weakness, fatigue, dry mouth, constipation andblurred vision.

Imipramine may cause blurred vision, dryness of mouth, constipation,urinary retention, orthostatic hypotension, respiration depression,myocardial infarction, and congestive heart failure. Similardifficulties are experienced with amitriptyline.

There is a continuing need for psychotherapeutic agents that have fewerside effects than the drugs in use today; also for psychotherapeuticagents that have different modes of action than presently used agents,since none of these is completely effective.

British Patent Specification No. 888,657 and Canadian Pat. No. 1,079,734disclose piperidinecarbinols, useful as analgesics and coughsuppressants, of the formula ##STR2## wherein X is phenyl;

Y is hydroxymethyl, 1-hydroxymethyl or 1-hydroxypropyl;

alk is alkylene of up to six carbon atoms;

and

R is an oxygen- or nitrogen-containing heterocyclic group,tetrahydrofurfuryloxyethyl, aryl, aryloxy, aralkoxy, alkoxy of up to sixcarbon atoms or alkoxy substituted by hydroxy, ethoxy or phenoxy.

Compounds of such structure wherein Y is alkanoyl and the othersubstituents are similarly defined are also known from British PatentSpecification No. 841,120.

Kagi et al., Helvetica Chimica Acta, Vol. XXXII, 2489 (1949) disclosethe synthesis of various analgesics; intermediate compounds of theformula ##STR3## wherein R₂ is CH₃ or n-C₃ H₇ are disclosed.

Lewis et al., J. Chem. Soc. C., 1970, 1074, disclose compounds of theformula ##STR4##

DISCLOSURE OF INVENTION

For further comprehension of the invention and of the objects andadvantages thereof, reference may be made to the following descriptionand to the appended claims in which the various novel features of theinvention are more particularly set forth.

The invention resides in 4-aryl-4-piperidinecarbinols of the formula##STR5## wherein (a) R¹ is H, alkyl of 1 to 12 carbon atoms, cycloalkylof 3 to 8 carbon atoms or benzyl;

(b) each of R² and R³ is independently selected from H and lower alkylof 1 to 4 carbon atoms; R¹ and R² taken together is a branched orunbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;or R² and R³ taken together is a branched or unbranched alkylene bridgewherein the bridge is of 3 to 6 carbon atoms;

(c) R⁴ is

(1) phenyl or 2-naphthyl or phenyl or 2-naphthyl substituted with one ortwo substituents, the same or different, selected from F, Cl, alkyl,perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy,perfluoroalkylthio and dialkylamino, said alkyl and alkoxy moietiesbeing of 1 to 12 carbon atoms and said aryl moieties being of 6 to 12carbon atoms;

(2) 2-, 3- or 4-biphenylyl or 2-, 3- or 4-biphenylyl wherein either orboth aromatic moieties is substituted with one or two substituents, thesame or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy,aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio anddialkylamino, said alkyl and alkoxy moieties being of 1 to 12 carbonatoms and said aryl moieties being of 6 to 12 carbon atoms;

(3) 2-pyrrolyl or 2-pyrrolyl substituted with one to three lower alkylgroups of 1 to 4 carbon atoms;

(4) 2-, 3-, or 4-pyridyl; or

(5) 2-thienyl substituted in the 5-position with lower alkyl of 1 to 4carbon atoms;

(d) each of R⁵ and R⁶ is independently selected from alkyl of 1 to 12carbon atoms and cycloalkyl of 3 to 8 carbon atoms or R⁵ and R⁶ takentogether is a branched or unbranched alkylene bridge wherein the bridgeis of 3 to 11 carbon atoms,

provided, however, when R¹, R⁵ and R⁶ are methyl and R² and R³ are H,then R⁴ is not p-t-butylphenyl or 2'-biphenylyl. The invention hereinalso resides in esters of the aforesaid piperidinecarbinols andaliphatic mono- and dicarboxylic acids of 1 to 8 carbon atoms; in aminesalts of the aforesaid piperidinecarbinols and pharmaceuticallycompatible inorganic acids; and in N-oxides of the aforesaidpiperidinecarbinols.

The 4-aryl-4-piperidinecarbinols of this invention can be prepared by aseries of reactions carried out in sequence as follows:

(1) R⁴ Br is lithiated with n-butyllithium to produce R⁴ Li which isthen reacted with the piperidinone of the formula: ##STR6## wherein R¹,R², R³ and R⁴ are as defined above,

to produce ##STR7## (2) I is dehydrated to the mixed olefins ##STR8##(3) II is lithiated with n-butyllithium and then reacted with the ketoneR⁵ COR⁶ wherein R⁵ and R⁶ are as defined above, to produce theoxaazabicyclooctane ##STR9## (4) III is reduced to produce IV.

Alternatively, II after lithiation can be reacted with the ester R⁵COOR⁷ wherein R₅ is as defined above and R⁷ is lower alkyl of 1 to 4carbon atoms, to produce the ketone ##STR10## which can then be reactedwith R⁶ Li or R⁶ MgX wherein R⁶ is as defined above and X is Cl, Br orI, to produce III. As is apparent, this alternate method cannot be usedif R⁵ and R⁶ taken together in IV is alkylene.

Following are more specific details of the reactions outlined above. Itis to be understood that the above outline is not intended to belimiting.

(1) Preparation of I

Lithiation of R⁴ Br can be carried out at -100° C. to 50° C. in anethereal solvent, for example, diethyl ether or tetrahydrofuran. Knowncommonly used lithiating agents include, for example, n-butyllithium,methyllithium and sec- and tert-butyllithium. As known in the art, amagnesium (Grignard) reagent may be used instead of the alkyl lithiumcompound, in which event the intermediate produced is an organomagnesiumcompound. Also as known in the art, for example, as disclosed byGschwend and Rodriguez, Organic Reactions, Volume 26, some compounds R⁴H wherein R⁴ is as defined above can be lithiated directly rather thanvia the intermediate R⁴ Br. Tetramethylethylenediamine may be employedin conjunction with the alkyl lithium compound. Such directly-lithiatedcompounds include the alkoxybenzenes, wherein lithiation occurs ortho tothe alkoxy substituent, and pyrrole and 5-alkylthiophenes, whereinlithiation occurs at the 2-positions.

In the second step of the preparation of I, the organolithium ororganomagnesium compound is reacted with the aforesaid piperidinoneeither neat or in an ethereal solvent, for example, diethyl ether ortetrahydrofuran, at -70° C. to 50° C.

(2) Preparation of II

The dehydration of I to II can be carried out in the presence of acatalyst, such as hydrochloric acid, hydrobromic acid, methanesulfonicacid/phosphorus pentoxide, trifluoroacetic acid or an arylsulfonic acid,either in a solvent, such as an aromatic hydrocarbon, or in the absenceof a solvent. Depending on the nature of the substituents R¹, R², R³ andR⁴, the dehydration can be carried out at an appropriate temperaturewithin the range 0° C. to 200° C. After dehydration the acid catalyst isneutralized to convert the amine salt to the free amine II.

(3) Preparation of III

Compound II can be metalated as described above in connection with thepreparation of I. Lithiation can be carried out at -70° C. to 70° C.,preferably at -10° C. to -20° C., in the absence of both oxygen andwater. The metal salt, in solution, thus produced can be reacted withthe aforesaid ketone R⁵ COR⁶ in an ethereal solvent, for example,diethyl ether or tetrahydrofuran, at -100° C. to 50° C. Upon hydrolysisof the resultant lithium or magnesium salt, III is obtained.

(4) Preparation of IV

Reduction of III provides IV. The reduction can be effected by means ofborohydride reagents, such as sodium borohydride in an alcohol or sodiumcyanoborohydride in an alcohol/acetic acid mixture, or by means ofcatalytic hydrogenation, for example, using a palladium catalyst, in anacetic acid or alcohol solvent in the presence of a mineral acid.

In the aforesaid alternative procedure, the metalated II, in solution,can be reacted with the ester R⁵ COOR⁷ to produce V which is reactedwith R⁶ Li or R⁶ MgX in an ethereal solvent at -20° C. to 50° C. Uponhydrolysis of the resultant lithium or magnesium salt, III is obtained.

In any of the aforesaid procedures wherein are present compounds havingthe piperidine moiety, the N-substituent can be benzyl instead of R¹, inwhich case the ultimate product is IV except that the N-substituent isbenzyl instead of R¹. The N-benzylated product is a valuableintermediate and can be converted by catalytic hydrogenolysis, using apalladium catalyst in an acetic acid solvent, to the secondary amine,that is, IV wherein R¹ is H. The secondary amine can be alkylated bymeans of the appropriate alkyl or cycloalkyl halide to produce IVwherein R¹ is alkyl of 1 to 12 carbon atoms or cycloalkyl of 3 to 8carbon atoms. Some of the R¹ groups can be introduced by an alternatemethod in which the secondary amine is first acylated with an acylchloride, the acyl group of which corresponds, when reduced, to thedesired R¹ group. The amide which is produced by acylation can bereduced with a hydride reducing agent, such as BH₃ or LiAlH₄, to providethe desired amine IV.

Suitable salts with pharmacologically acceptable acids, such ashydrochloric, sulfuric, phosphoric, and maleic acids, may be preparedfrom all free bases IV. Such salts may be preferable when the free basesare oils. Salts of bases IV may also be more stable to storage, and maybe better absorbed orally, than the free bases.

In the following examples, all temperatures are in degrees Celsius.Table 1 summarizes the compounds prepared in the examples. In the table"Me" is CH₃, "Et" is C₂ H₅, "Ph" is C₆ H₅, "PhCH₂ " is benzyl and "Cp"is cyclopentyl.

                                      TABLE 1                                     __________________________________________________________________________    Ex.                                                                           No.                                                                              R.sup.1                                                                           R.sup.2                                                                          R.sup.3                                                                          R.sup.4    R.sup.5                                                                              R.sup.6                                        __________________________________________________________________________     1 Me  H  H  Ph         Me     Me                                              2 Me  H  H  m-CF.sub.3 C.sub.6 H.sub.4                                                               Me     Me                                              3 Me  H  H  2,3-(MeO).sub.2 C.sub.6 H.sub.3                                                          (CH.sub.2).sub.4                                       4 Me  H  H  m-FC.sub.6 H.sub.4                                                                       Me     Me                                              5 Me  H  H  p-FC.sub.6 H.sub.4                                                                       Me     Me                                              6 Me  H  H  m-ClC.sub.6 H.sub.4                                                                      Me     Me                                              7 Me  H  H  p-ClC.sub.6 H.sub.4                                                                      Me     Me                                              8 Me  H  H  m-ClC.sub.6 H.sub.4                                                                      Et     Et                                              9 Me  H  H  o-MeC.sub.6 H.sub.4                                                                      Me     Me                                             10 Me  H  H  m-MeC.sub.6 H.sub.4                                                                      Me     Me                                             11 Me  H  H  p-MeC.sub.6 H.sub.4                                                                      Me     Me                                             12 Me  H  H  3,5-Me.sub.2 C.sub.6 H.sub.3                                                             Me     Me                                             13 Me  H  H  3,4-Me.sub.2 C.sub.6 H.sub.3                                                             Me     Me                                             14 H   H  H  m-MeOC.sub.6 H.sub.4                                                                     Me     Me                                             15 Me  H  H  o-MeOC.sub.6 H.sub.4                                                                     Me     Me                                             16 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     Me     Me                                             17 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     Me     Et                                             18 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     Et     Et                                             19 Me  H  H  p-MeOC.sub.6 H.sub.4                                                                     Me     Me                                             20 Me  H  H  2,3-(MeO).sub.2 C.sub.6 H.sub.3                                                          Me     Me                                             21 Me  H  H  p-MeSC.sub.6 H.sub.4                                                                     Me     Me                                             22 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3                                      23 Me  H  H  2,3-(MeO).sub.2 C.sub.6 H.sub.3                                                          (CH.sub.2).sub.5                                      24 Me  H  H                                                                                 ##STR11## Me     Me                                               25                                                                             Me  H  H                                                                                 ##STR12## Me     Me                                               26                                                                             Me  H  H                                                                                 ##STR13## Me     Me                                             27 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.6                                      28 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.7                                      29 Me  H  H  2,5-(MeO).sub.2 C.sub.6 H.sub.3                                                          Me     Me                                             30 Me  H  H  m-CF.sub.3 C.sub.6 H.sub.4                                                               (CH.sub.2).sub.4                                      31 Me  H  H  m-CF.sub.3 C.sub.6 H.sub.4                                                               Me     Et                                             32 Me  H  H  p-PhOC.sub.6 H.sub.4                                                                     Me     Me                                             33 Me  H  H  p-Me.sub.2 NC.sub.6 H.sub.4                                                              Me     Me                                             34 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.4                                      35 Me  H  H  m-MeOC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.5                                      36 Me  H  H  m-PhC.sub.6 H.sub.4                                                                      Me     Me                                             37 PhCH.sub.2                                                                        H  H  2,3-(MeO).sub.2 C.sub.6 H.sub.3                                                          Me     Me                                             38 PhCH.sub.2                                                                        H  H  2,3-(MeO).sub.2 C.sub.6 H.sub.3                                                          (CH.sub.2).sub.4                                      39 Me  H  H  6'-methoxy-2'-naphthyl                                                                   Me     Me                                             40 Me  H  H  m-EtOC.sub.6 H.sub.4                                                                     Me     Me                                             41 Et  H  H  m-CF.sub.3 C.sub.6 H.sub.4                                                               Me     Me                                             42 Me  H  H  4'-biphenylyl                                                                            Me     Me                                             43 Me  H  CH.sub.3                                                                         m-CH.sub.3 OC.sub.6 H.sub.4                                                              Me     Me                                             44 Me  CH.sub.3                                                                         H  m-CH.sub.3 C.sub.6 H.sub.4                                                               Me     Me                                             45 (CH.sub.2).sub.3                                                                     H  m-CF.sub.3 C.sub.6 H.sub.4                                                               Me     Me                                             46*                                                                              Me  H  H  m-CF.sub.3 C.sub.6 H.sub.4                                                               CH.sub.2 CH.sub.2.sup.+CH(CH.sub.3)CH.sub.2             47**                                                                           Me  H  H  m-CF.sub.3 C.sub.6 H.sub.4                                                               CH.sub.2 CH.sub.2.sup.±CH(CH.sub.3)CH.sub.2        __________________________________________________________________________     *dl-mixture of cis and trans isomers.                                         **1mixture of cis and trans isomers.                                          .sup.+ epimers at this position.                                              .sup.± single configuration at this position.                         

Table 1A includes additional preferred embodiments of the invention;these embodiments, however, are not exemplified herein.

                  TABLE 1A                                                        ______________________________________                                        Ex.                                                                           No.  R.sup.1 R.sup.2                                                                              R.sup.3                                                                             R.sup.4  R.sup.5                                                                              R.sup.6                             ______________________________________                                        1    Me      H      H     m-CF.sub.3 C.sub.6 H.sub.4                                                              ##STR14##                                   2  Me      H      H     m-CF.sub.3 C.sub.6 H.sub.4                                                              ##STR15##                                                 3    Me    H    H     m-CF.sub.3 OC.sub.6 H.sub.4                                                            Me                                                       Me                                                                            4 Me H H m-CF.sub.3 SC.sub.6 H.sub.4 Me Me                                    5 Cp H H m-CF.sub.3 C.sub.6 H.sub.4 Me Me           6    Me     (CH.sub.2).sub.3                                                                          m-CF.sub.3 C.sub.6 H.sub.4                                                             Me     Me                                    7    Me     (CH.sub.2).sub.4                                                                          m-CF.sub.3 C.sub.6 H.sub.4                                                             Me     Me                                    8    Me     (CH.sub.2).sub.6                                                                          m-CF.sub.3 C.sub.6 H.sub.4                                                             Me     Me                                    9    (CH.sub.2).sub.4                                                                         H       m-CF.sub.3 C.sub.6 H.sub.4                                                             Me     Me                                    10   Me      H      H     2-pyridyl                                                                              Me     Me                                  11   Me      H      H     4-pyridyl                                                                              Me     Me                                  12   Me      H      H     m-C.sub.2 F.sub.5 C.sub.6 H.sub.4                                                      Me     Me                                  13   Me      H      H     m-PhSC.sub.6 H.sub.4                                                                   Me     Me                                  ______________________________________                                    

EXAMPLE 1 4-Phenyl-α,α,1-trimethyl-4-piperidinemethanol

n-Butyllithium (15 ml of 1.5M solution in hexane) was added undernitrogen to a solution of 4.7 g of commercially available1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (II: R¹ =Me; R², R³ =H; R⁴=phenyl) in 50 mL of tetrahydrofuran, kept at -10°. The deep redsolution was stirred at -10° for 15 min and then transferred in a slowstream into a stirred mixture of 15 mL of acetone and 25 mL oftetrahydrofuran and kept at -70°. Excess 10% hydrochloric acid was addedafter stirring at -70° for 5 min; the mixture was allowed to come toroom temperature, and then washed with toluene. The aqueous layer wasmade basic with sodium hydroxide and extracted with methylene chloride.Removal of the solvent from the dried solution and short-pathdistillation of the residue (90°-135° bath temperature, 5×10⁻⁴ mm Hg[0.07 Pa]) gave 2.79 g of5-phenyl-2,6,6-trimethyl-7-oxa-2-azabicyclo[3.2.1]octane (III: R¹, R⁵,R⁶ =Me; R², R³ =H, R⁴ =phenyl) as an oil of ca. 85% purity.

A solution of 1.47 g of the above product III in a mixture of 10 mL ofmethanol and 2 mL of acetic acid was cooled with ice and treated with0.76 g of sodium cyanoborohydride. The mixture was stirred at roomtemperature for 2 h, and the excess borohydride was decomposed byaddition, with ice cooling, of 8 mL of conc hydrochloric acid. Afterstirring at room temperature for 0.5 h the mixture was made basic withaqueous sodium hydroxide solution and extracted with methylene chloride.Removal of the solvent from the dried solution and crystallization ofthe residue from ethyl acetate gave 0.98 g of4-phenyl-α,α,1-trimethyl-4-piperidinemethanol, m.p. 146°-147°. NMR (220MHz in CDCl₃): τ 2.7-2.8 (m, 5H); 7.0-8.2 (m, 9H); 8.0 (s, 3H) and 8.9(s, 6H). Anal. Calcd. for C₁₅ H₂₃ NO: C, 77.21; N, 9.94; N, 6.00. Found:C, 77.12; H, 9.89; N, 6.00.

EXAMPLE 24-(3'-Trifluoromethylphenyl)-α,α,1-trimethyl-4-piperidinemethanol andits Hydrochloride

A 1.5M solution of n-butyllithium in hexane (150 mL) was added undernitrogen at -70° to a stirred solution of 50 mg of3-bromobenzotrifluoride in 300 mL of tetrahydrofuran. The mixture wasstirred at -70° for 15 min and then allowed to warm to -20°. A solutionof 30 g of freshly distilled 1-methyl-4-piperidone in 50 mL oftetrahydrofuran was added slowly, keeping the temperature at -20°. Themixture was then stirred at 0° for 0.5 h, and at room temperature for 3h. Water and methylene chloride were added and the aqueous layer wasextracted several times with methylene chloride. Removal of the solventfrom the combined and dried methylene chloride solutions, and short-pathdistillation of the residue (110°-130° bath temp., 5×10⁻⁴ mm Hg [0.07Pa]) gave 41.6 g of 1-methyl-4-(3'-trifluoromethylphenyl)-4 -piperidinol(I: R¹ =Me; R², R³ =H; R⁴ =m-trifluoromethylphenyl) as a solid.

A mixture of 28.1 g of this product I and 100 mL of trifluoroacetic acidwas heated under reflux for 24 h. The excess acid was removed undervacuum, the residue was dissolved in methylene chloride and the solutionwas made basic with 10% aqueous sodium carbonate solution. Removal ofthe solvent from the dried organic phase and short-path distillation ofthe residue gave 24.06 g of1-methyl-4-(3'-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (IIa:R¹ =Me; R², R³ =H; R⁴ =m-trifluoromethylphenyl).

To a solution of this product IIa in 150 mL of tetrahydrofuran wasadded, at -10°, 80 mL of a 1.5M solution of n-butyllithium in hexane.The red solution was stirred at -10° for 15 min and then transferred ina slow stream into a stirred mixture of 60 mL of acetone and 60 mL oftetrahydrofuran, kept at -20°. The mixture was allowed to come to 10°and was then treated with 10% aqueous sodium chloride solution. Thelayers were separated and the aqueous phase was extracted repeatedlywith methylene chloride. Removal of the solvent from the combined, driedorganic phases gave 34.35 g of crude5-(3'-trifluoromethylphenyl)-2,6,6-trimethyl-7-oxa-2-azabicyclo[3.2.1]octane(III: R¹, R⁵, R⁶ =Me; R², R³ =H; R⁴ =m-trifluoromethylphenyl). Thisproduct III was dissolved in a mixture of 150 mL of methanol and 25 mLof acetic acid and the solution, ice cooled, was treated with 9 g ofsodium cyanoborohydride. Concentrated hydrochloric acid (50 mL) wasadded after stirring at room temperature for 2 h, and after a further0.5 h, the mixture was made basic with aqueous sodium hydroxide solutionand extracted with methylene chloride. Removal of the solvent from thedried organic phases gave 31.74 g of a product which was partitionedbetween dilute hydrochloric acid and ether/toluene. Rebasification ofthe aqueous phase followed by methylene chloride extraction gave 27.40 gof product. Short-path distillation (to 210° bath temp., 10⁻³ mm Hg [0.1Pa]) and crystallization of the distillate from cyclohexane gave 7.59 gof 4-(3'-trifluoromethylphenyl)-α,α,1-trimethyl-4-piperidinemethanol,m.p. 111°-112°. NMR (90 MHz in CDCl₃): τ2.3-2.6 (m, 4H); 7.1-8.3 (m,9H); 7.8 (s, 3H) and 8.8 (s, 6H); ¹⁹ F NMR (in CDCl₃): singlet at -63.02ppm from CFCl₃. The hydrochloride (referred to in Table 2 as Example 2A)had a m.p. of 240°-241° after crystallization from isopropyl alcohol.Anal. Calcd. for C₁₆ H₂₃ ClF₃ NO: C, 56.89; H, 6.86; N, 4.15. Found: C,57.03; H, 6.78; N, 4.07.

EXAMPLE 31-[1'-Methyl-4'-(2",3"-dimethoxyphenyl)-4'-piperidinyl]cyclopentanol

A solution of 138 g of veratrole in 400 mL of dry tetrahydrofuran wascooled in a dry ice/acetone bath and treated with 500 mL of a 1.6Msolution of n-butyllithium at such a rate that the temperture of thereaction mixture remained at 0°. After the addition was completed thereaction mixture was stirred at room temperature for 3 h. At the end ofthis period the resulting white slurry was cooled in a dry ice/acetonebath and 90.4 g of 1-methyl-4-piperidone was added at such a rate thatthe temperature of the reaction mixture remained below -10°. After theaddition was completed the reaction mixture was stirred at 0° for 2 h,quenched with 400 mL of water and diluted with 400 mL of ether. Theorganic layer was separated and the aqueous layer was extracted withmethylene chloride (3×400 mL). The combined organic layers were dried(K₂ CO₃) and concentrated under reduced pressure to afford 270.9 g of anoil. This oil was heated under reduced pressure to remove all thematerial boiling below 150°/0.025 mm Hg (3.3 Pa). The residue (97.55 g)contained the desired 4-(2',3'-dimethoxyphenyl)-1-methyl-4-piperidinol(I: R¹ =Me, R², R³ =H; R⁴ =2,3-dimethoxyphenyl) and was used withoutfurther purification in the next step.

A solution of 79.49 g of this product I in 238 mL of conc hydrochloricacid was heated to 65° for 3 h. At the end of this period the reactionmixture was cooled to room temperature, made basic with 20% aqueoussodium hydroxide solution, and extracted with portions (3×200 mL) ofmethylene chloride; the combined organic layers were dried (K₂ CO₃) andconcentrated under reduced pressure. The product thus obtained wasdistilled under reduced pressure to yield4-(2',3'-dimethoxyphenyl)-1-methyl-1,2,3,6-tetrahydropyridine (IIa: R¹=Me; R², R³ =H; R⁴ =2,3-dimethoxyphenyl) as a colorless oil, bp100°-120°/0.05 mm Hg (7 Pa), 73.56 g (84.8% yield).

A solution of 4.7 g of this product IIa in 50 mL of tetrahydrofuran wastreated with n-butyllithium as described in Example 1 and the solutionof the lithium salt was added to a mixture of 20 mL of cyclopentanoneand 30 mL of tetrahydrofuran at -70°. Isolation as described in Example1 and crystallization of the crude product from ethyl acetate gave 3.29g of2'-methyl-5'-(2",3"-dimethoxyphenyl)spiro[cyclopentane-1,6'-[7]-oxa[2]azabicyclo[3.2.1]octane](III: R¹ =Me; R², R³ =H; R⁴ =2,3-dimethoxyphenyl; R⁵, R⁶ =(CH₂)₄), m.p.110°. Anal. Calcd. for C₁₉ H₂₇ NO₃ : C, 71.89; H, 8.57; N, 4.41. Found:C, 72.24; H, 8.45; N, 4.52.

Reduction of the immediately preceding product with sodiumcyanoborohydride as described in Example 1 gave1-[1'-methyl-4'-(2",3"-dimethoxyphenyl)-4'-piperidinyl]cyclopentanol,m.p. 114°-115°. Anal. Calcd. for C₁₉ H₂₉ NO₃ : C, 71.44; H, 9.15; N,4.38. Found: C, 71.49; H, 9.01; N, 4.41.

EXAMPLE 4 4-(3'-Fluorophenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(3'-Fluorophenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 3-bromofluorobenzene by the procedure described in Example 2; m.p.158°-159°; NMR (in CDCl₃): τ2.5-3.2 (m, 4H); 7.2-8.3 (m, 12H) and 8.8(s, 6H); ¹⁹ F NMR (in CDCl₃): singlet (after H-decoupling) at -117.4 ppmfrom CFCl₃. Anal. Calcd. for C₁₅ H₂₂ FNO: C, 71.68; H, 8.82; N, 5.57.Found: C, 71.68; H, 8.77; N, 5.69.

EXAMPLE 5 4-(4'-Fluorophenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Fluorophenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 4-bromofluorobenzene by the procedure described in Example 2; m.p.165°-166°; NMR (in CDCl₃): τ2.6-3.1 (m, 4H); 7.2-8.7 (m, 12H) and 8.9(s, 6H); ¹⁹ F NMR (in CDCl₃): singlet (after H-decoupling) at -117.6 ppmfrom CFCl₃. Anal. Calcd. for C₁₅ H₂₂ FNO: C, 71.68; H, 8.82; N, 5.57.Found: C, 71.26; H, 8.70; N, 5.67.

EXAMPLE 6 4-(3'-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(3'-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 3-bromofluorobenzene using the procedure described in Example 2;m.p. 149°-150°; NMR (in CDCl₃): τ2.6-2.8 (m, 4H); 7.1-8.3 (m, 12H) and8.8 (s, 6H). Anal. Calcd. for C₁₅ H₂₂ ClNO: C, 67.28; H, 8.28; N, 5.23.Found: C, 67.34; H, 8.15; N, 5.24.

EXAMPLE 7 4-(4'-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 4-bromofluorobenzene using the procedure described in Example 2;m.p. 192°-194°. Anal. Calcd. for C₁₅ H₂₂ ClNO: C, 67.28; H, 8.28; N,5.23. Found: C, 67.34; H, 8.13; N, 5.25.

EXAMPLE 8 4-(3'-Chlorophenyl)-α,α-diethyl-1-methyl-4-piperidinemethanoland its Hydrochloride

4-(3'-Chlorophenyl)-α,α-diethyl-1-methyl-4-piperidinemethanol wasprepared from 3-bromochlorobenzene by the procedure described in Example2 except that diethylketone (3-pentanone) was used in place of acetonein the preparation of III. The free base was converted to thehydrochloride which had a m.p. of 249°-250° (dec) after crystallizationfrom ethanol; NMR (in CDCl₃): τ2.6 (m, 4H); 6.3-8.0 (m, 12H); 8.3-8.6(quartet, 4H) and 9.2 (t, 6H). Anal. Calcd. for C₁₇ H₂₇ Cl₂ NO: C,61.44; H, 8.19; N, 4.21. Found: C, 61.19; H, 8.19; N, 4.19.

EXAMPLE 9 4-(2'-Tolyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(2'-Tolyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from2-bromotoluene by the procedure described in Example 2; m.p. 104°-105°;NMR (in CDCl₃): τ2.5-3.0 (m, 4H); 7.0-8.3 (m, 15H) and 8.9 (s, 6H).Anal. Calcd. for C₁₆ H₂₅ NO: C, 77.68; H, 10.19; N, 5.66. Found: C,77.69; H, 10.19; N, 5.76.

EXAMPLE 10 4-(3'-Tolyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(3'-Tolyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from3-bromotoluene by the procedure described in Example 2; m.p. 139°-140°;NMR (in CDCl₃): τ2.6-3.1 (m, 4H); 7.2-8.5 (m, 15H) and 8.9 (s, 6H).Anal. Calcd. for C₁₆ H₂₅ NO: C, 77.68; H, 10.19; N, 5.66. Found: C,77.68; H, 10.12; N, 5.83.

EXAMPLE 11 4-(4'-Tolyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Tolyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from4-bromotoluene by the procedure described in Example 2; m.p. 172°-174°;NMR (in CDCl₃): τ2.6-3.0 (m, 4H); 7.2-8.5 (m, 15H) and 8.9 (s, 6H).Anal. Calcd. for C₁₆ H₂₅ NO: C, 77.68; H, 10.19; N, 5.66. Found: C,77.80; H, 10.23; N, 5.67.

EXAMPLE 12 4-(5'-m-Xylyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(5'-m-Xylyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from5-bromo-m-xylene by the procedure described in Example 2; m.p.123°-125°; NMR (in CDCl₃): τ3.0-3.2 (m, 3H); 7.2-8.6 (m, 18H) and 8.9(s, 6H). Anal. Calcd. for C₁₇ H₂₇ NO: C, 78.11; H, 10.41; N, 5.36.Found: C, 78.21; H, 10.19; N, 5.48.

EXAMPLE 13 4-(4'-o-Xylyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-o-Xylyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from4-bromo-o-xylene by the procedure described in Example 2; m.p.127°-128°; NMR (in CDCl₃): τ2.8-3.1 (m, 3H); 7.2-8.3 (m, 18H) and 8.9(s, 6H). Anal. Calcd. for C₁₇ H₂₇ NO: C, 78.11; H, 10.41; N, 5.36.Found: C, 78.43; H, 10.11; N, 5.40.

EXAMPLE 14 4-(3'-Methoxyphenyl)-α,α-dimethyl-4-piperidinemethanol andits Hydrochloride

1-Benzyl-4-(3'-methoxyphenyl)-α,α-dimethyl-4-piperidinemethanol wasprepared from 3-bromoanisole by the procedure described in Example 2except that 1-benzyl-4-piperidone was used in place of1-methyl-4-piperidone in the first step. This product (2.90 g) wasdissolved in 20 mL of acetic acid, 0.49 g of 10% Pd/C was added, and themixture was stirred under an atmosphere of hydrogen for 25 h. Themixture was filtered; the filtrate was concentrated, made basic, andextracted with methylene chloride to give 1.88 g of the crude free base(IV: R¹, R², R³ =H; R⁴ =m-MeOC₆ H₄ ; R⁵, R⁶ =Me). It was converted tothe hydrochloride salt which had a m.p. of 232°-233° (dec) aftercrystallization from acetonitrile. NMR (in D₂ O): τ2.6-3.3 (m, 4H); 6.3(s, 3H); 6.6-8.3 (m, 9H) and 9.0 (s, 6H). Anal. Calcd. for C₁₅ H₂₄ ClNO₂: C, 63.04; H, 8.46; N, 4.90. Found: C, 63.19; H, 8.41; N, 4.87.

EXAMPLE 15 4-(2'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(2'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom anisole by the procedure described in Example 3 except that acetonewas used in place of cyclopentanone in the preparation of III; m.p.110°-111°; NMR (in CDCl₃): τ2.6-3.1 (m, 4H); 6.2 (s, 3H); 6.7-8.5 (m,9H); 7.9 (s, 3H) and 8.9 (broad s, 6H). Anal. Calcd. for C₁₆ H₂₅ NO₂ :C, 72.96; H, 9.57; N, 5.32. Found: C, 73.02; H, 9.56; N, 5.41.

EXAMPLE 16 4-(3'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(3'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 3-bromoanisole by the procedure described in Example 2; m.p. 100°;NMR (in CDCl₃): τ2.6-3.3 (m, 4H); 6.1 (s, 3H); 7.1-8.3 (m, 12H); 8.9 (s,6H). Anal. Calcd. for C₁₆ H₂₅ NO₂ : C, 72.96; H, 9.57; N, 5.32. Found:C, 72.52; H, 9.42; N, 5.29.

EXAMPLE 174-(3'-Methoxyphenyl)-α,1-dimethyl-α-ethyl-4-piperidinemethanol

4-(3'-Methoxyphenyl)-α,1-dimethyl-α-ethyl-4-piperidinemethanol wasprepared from 3-bromoanisole by the procedure described in Example 2except that methyl ethyl ketone (2-butanone) was used in place ofacetone in the preparation of III; m.p. 134°-135°; NMR (in CDCl₃):τ2.6-3.3 (m, 4H); 6.2 (s, 3H); 7.2-8.3 (m, 12H); 8.6 (quartet, 2H); 9.0(s, 3H) and 9.2 (t, 3H). Anal. Calcd. for C₁₇ H₂₇ NO₂ : C, 73.61; H,9.81; N, 5.05. Found: C, 73.73; H, 9.69; N, 5.17.

EXAMPLE 184-(3'-Methoxyphenyl)-α,α-diethyl-1-methyl-4-piperidinemethanol and itsHydrochloride

4-(3'-Methoxyphenyl)-α,α-diethyl-1-methyl-4-piperidinemethanol wasprepared from 3-bromoanisole by the procedure described in Example 2except that diethyl ketone was used in place of acetone in thepreparation of III. The product IV was converted to the hydrochloridewhich had a m.p. of 197°-198° (dec) after crystallization from isopropylalcohol; NMR (in CDCl₃): τ2 (broad s, 1H); 2.5-3.2 (m, 4H); 6.1 (s, 3H);6.3-8.6 (m, 16H); and 9.2 (t, 6H). Anal. Calcd. for C₁₈ H₃₀ ClNO₂ : C,65.93; H, 9.22; N, 4.27. Found: C, 65.91; H, 9.14; N, 4.72.

EXAMPLE 19 4-(4'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Methoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 4-bromoanisole by the procedure described in Example 2; m.p.114°-115°; NMR (in CDCl₃): τ2.6-3.2 (m, 4H); 6.2 (s, 3H); 7.2-8.5 (m,12H) and 8.9 (s, 6H). Anal. Calcd. for C₁₆ H₂₅ NO₂ : C, 72.96; H, 9.57;N, 5.32. Found: C, 72.63; H, 9.47; N, 5.39.

EXAMPLE 204-(2',3'-Dimethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(2',3'-Dimethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared by the procedure described in Example 3 except that acetone wasused in place of cyclopentanone in the preparation of III; m.p. 97°; NMR(in CDCl₃): τ2.9-3.3 (m, 3H); 6.2 (2s, 6H); 6.7-8.5 (12H) and 8.9(broad, 6H). Anal. Calcd. for C₁₇ H₂₇ NO₃ : C, 69.59; H, 9.28; N, 4.77.Found: C, 69.93; H, 9.17; N, 4.81.

EXAMPLE 21 4-(4'-Methylthiophenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Methylthiophenyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared from 4-bromothioanisole by the procedure described in Example2; m.p. 132°-133°; NMR (in CDCl₃): τ2.7 (s, 4H); 7.2-8.5 (m, +2s, 15H)and 8.9 (s, 6H). Anal. Calcd. for C₁₆ H₂₅ NOS: C, 68.77; H, 9.02; N,5.01. Found: C, 68.82; H, 8.93; N, 5.12.

EXAMPLE 221-[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidinyl]cyclobutanol

1-[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidinyl]cyclobutanol wasprepared from 3-bromoanisole by the procedure described in Example 2except that cyclobutanone was used in place of acetone in thepreparation of III; m.p. 105°; NMR (360 MHz in CDCl₃): τ 2.5 (t, 1H);3.1 (d, split further, 1H); 3.1 (t, 1H); 3.2 (d/d, 1H); 6.2 (s, 3H); 7.8(s, 3H) and 7.2-8.8 (m, 15H).

EXAMPLE 231-[1'-Methyl-4'-(2",3"-dimethoxyphenyl)-4'-piperidinyl]cyclohexanol

1-[1'-Methyl-4'-(2",3"-dimethoxyphenyl)-4'-piperidinyl]cyclohexanol wasprepared by the procedure described in Example 3 except thatcyclohexanone was used in place of cyclopentanone in the synthesis ofIII; m.p. 121°-123°; NMR (in CDCl₃): τ3.1 (t, 1H); 3.2 (m, 2H); 6.2 (2s,6H); 7.0-7.3 (m, 4H); 7.7-9.1 (15H) and 7.9 (s, 3H). Anal. Calcd. forC₂₀ H₃₁ NO₃ : C, 72.03; H, 9.37; N, 4.20. Found: C, 71.58; H, 9.22; N,4.48.

EXAMPLE 244-(1'-Methyl-2'-pyrrolyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(1'-Methyl-2'-pyrrolyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared by the procedure described in Example 3 except that1-methylpyrrole was used in place of veratrole in the preparation of Iand acetone was used in place of cyclopentanone in the preparation ofIII; m.p. 110°-111°; NMR (in CDCl₃): τ3.5 (m, 1H); 4.0 (m, 2H); 6.2 (s,3H); 7.1-8.5 (m, 12H) and 8.8 (s, 6H).

EXAMPLE 25 4-(5'-Methyl-2'-thienyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(5'-Methyl-2'-thienyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared by the procedure described in Example 3 except that2-methylthiophene was used in place of veratrole in the preparation of Iand acetone was used in place of cyclopentanone in the preparation ofIII; m.p. 113°-114°; NMR (360 MHz in CDCl₃): τ3.35 (AB quartet, J=3.5Hz, lower-field compound split into quartets, J=0.7 Hz; 2H); 7.3 (m,2H); 7.5 (d, J=0.7 Hz, 3H); 7.8 (s, 3H); 8.0 (m, 6H); 8.4 (broad s, 1H)and 8.8 (s, 6H).

EXAMPLE 26 4-(3'-Pyridyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(3'-Pyridyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from3-bromopyridine by the procedure described in Example 2 except that thedehydration of the carbinol I was carried out by heating withtrifluoroacetic acid to 180° instead of under reflux; m.p. 131°-133°;NMR (360 MHz in CDCl₃): τ1.4 (d, J=2.5 Hz, 1H); 1.5 (d/d, J=4.5/1.5 Hz,1H); 2.3 (d/t, J=8.5/2 Hz, 1H); 2.7 (d/d, J=8.5/4.5 Hz, 1H); 7.2 (d,split further, 2H); 7.6 (d, 2H); 7.8-7.9 (m+s, 5H); 8.1 (broad s, 1H)and 8.8 (s, 6H).

EXAMPLE 271-[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidinyl]cycloheptanol

1-[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidinyl]cycloheptanol wasprepared from 3-bromoanisole by the procedure described in Example 2except that cycloheptanone was used in place of acetone in thepreparation of III; m.p. 139°-140°; NMR (in CDCl₃): τ 2.6-3.3 (m, 4H);6.2 (s, 3H) and 7.2-9.0 (m+s, 24H). Anal. Calcd. for C₂₀ H₃₁ NO₂ : C,75.67; H, 9.84; N, 4.41. Found: C, 76.23; H, 9.64; N, 4.28.

EXAMPLE 281-[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidinyl]cyclooctanol

1-[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidinyl]cyclooctanol wasprepared from 3-bromoanisole by the procedure described in Example 2except that cyclooctanone was used in place of acetone in thepreparation of III; m.p. 120°-122°; NMR (in CDCl₃): τ 2.6-3.3 (m, 4H);6.2 (s, 3H) and 7.2-9.0 (m+s, 26H). Anal. Calcd. for C₂₁ H₃₃ NO₂ : C,76.09; H, 10.03; N, 4.33. Found: C, 76.11; H, 9.70; N, 4.09.

EXAMPLE 294-(2',5'-Dimethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(2',5'-Dimethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared from 1,4-dimethoxybenzene by the procedure described in Example3 except that acetone was used in place of cyclopentanone in thesynthesis of III; m.p. 139°-140°; NMR (in CDCl₃): τ 3.0-3.3 (m, 3H); 6.2(2s, 6H); 6.6-8.5 (m+s, 12H) and 8.9 (broad, 6H). Anal. Calcd. for C₁₇H₂₇ NO₃ : C, 69.59; H, 9.29; N, 4.77. Found: C, 69.66; H, 9.09; N, 4.66.

EXAMPLE 301-[1'-Methyl-4'-(3"-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanol

1-[1'-Methyl-4'-(3"-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanolwas prepared by the procedure described in Example 2 except thatcyclopentanone was used in place of acetone in the preparation of III;m.p. 137°-138°. Anal. Calcd. for C₁₈ H₂₄ F₃ NO: C, 66.04; H, 7.34; N,4.09. Found: C, 66.14; H, 7.23; N, 4.09.

EXAMPLE 314-(3'-Trifluoromethylphenyl)-α,1-dimethyl-α-ethyl-4-piperidinemethanoland its Hydrochloride

4-(3'-Trifluoromethylphenyl)-α,1-dimethyl-α-ethyl-4-piperidinemethanolwas prepared by the procedure described in Example 2 except that methylethyl ketone was used in place of acetone in the preparation of III. Theproduct IV was converted to the hydrochloride salt which had a m.p. of227°-228° (dec); NMR (360 MHz in CDCl₃): τ 2.4-2.5 (m, 4H); 6.5 (m, 2H);7.0-7.6 (m, 10H); 8.5 (m, 1H); 8.8 (m, 1H); 8.9 (s, 3H) and 9.1 (t, 3H).

EXAMPLE 32 4-(4'-Phenoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Phenoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom p-bromophenyl phenyl ether by the procedure described in Example 2;m.p. 148°. Anal. Calcd. for C₂₁ H₂₇ NO₂ : C, 77.50; H, 8.36; N, 4.30.Found: C, 77.25; H, 8.13; N, 4.33.

EXAMPLE 334-(4'-Dimethylaminophenyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Dimethylaminophenyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared from p-bromo-N,N-dimethylaniline by the procedure described inExample 2 except that the dehydration of the carbinol was carried out byheating with trifluoroacetic acid in a sealed tube to 140° for 4 hinstead of under reflux; m.p. 142°-143°. Anal. Calcd. for C₁₇ H₂₈ N₂ O:C, 73.87; H, 10.21; N, 10.13. Found: C, 73.89; H, 10.15; N, 10.27.

EXAMPLE 34 1[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidine]cyclopentanol

1[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidine]cyclopentanol wasprepared from m-bromoanisole by the procedure described in Example 2except that cyclopentanone was used in place of acetone in thepreparation of III; m.p. 108°-109°. Anal. Calcd. for C₁₈ H₂₇ NO₂ : C,74.70; H, 9.40; N, 4.84. Found: C, 74.99; H, 9.12; N, 5.03.

EXAMPLE 35 1[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidine]cyclohexanol

1[1'-Methyl-4'-(3"-methoxyphenyl)-4'-piperidine]cyclohexanol wasprepared from m-bromoanisole by the procedure described in Example 2except that cyclohexanone was used in place of acetone in thepreparation of III. The product IV was converted to the hydrochloridesalt which had a m.p. of 255° (dec); NMR (in CDCl₃): τ 2.5-2.8 (m, 1H);3.0-3.3 (m, 2H); 6.2 (s, 3H) and 6.4-9.3 (m, 22H).

EXAMPLE 36 4-(3'-Biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol andits Hydrochloride

4-(3'-Biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from3-bromobiphenyl by the procedure described in Example 2. The product IVwas converted to the hydrochloride salt which had a m.p. of 221°-223°(dec); NMR (in CDCl₃): τ 2.2-2.7 (m, 9H); 6.3-7.7 (m, 12H) and 8.7 (s,6H).

EXAMPLE 374-(2',3'-Dimethoxyphenyl)-1-benzyl-α,α-dimethyl-4-piperidinemethanol andits Hydrochloride

4-(2',3'-Dimethoxyphenyl)-1-benzyl-α,α-dimethyl-4-piperidinemethanol wasprepared by the procedure described in Example 3 except that1-benzyl-4-piperidone was used in place of 1-methyl-4-piperidone in thepreparation of I and acetone was used in place of cyclopentanone in thepreparation of III. The product IV was converted to the hydrochloridesalt which had a m.p. of 236°-237° (dec) after crystallization fromacetonitrile. Anal. Calcd. for C₂₃ H₃₂ ClNO₃ : C, 68.05; H, 7.95; N,3.45. Found: C, 68.37; H, 7.80; N, 3.69.

EXAMPLE 381-[1'-Benzyl-4'-(2",3"-dimethoxyphenyl)-4'-piperidinyl]cyclopentanol andits Hydrochloride

1-[1'-Benzyl-4'-(2",3"-dimethoxyphenyl)-4'-piperidinyl]cyclopentanol wasprepared by the procedure described in Example 3 except that1-benzyl-4-piperidone was used in place of 1-methyl-4-piperidone in thefirst step. The product IV was converted to the hydrochloride salt whichhad a m.p. of 235° (dec) after crystallization from 90% ethanol. Anal.Calcd. for C₂₅ H₃₄ ClNO₃ : C, 69.51; H, 7.93; N, 3.24. Found: C, 69.29;H, 7.71; N, 3.59.

EXAMPLE 394-(6'-Methoxy-2'-naphthyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(6'-Methoxy-2'-naphthyl)-α,α,1-trimethyl-4-piperidinemethanol wasprepared from 2-bromo-6-methoxynaphthalene by the procedure described inExample 2; m.p. 170°-171°. Anal. Calcd. for C₂₀ H₂₇ NO₂ : C, 76.64; H,8.68; N, 4.47. Found: C, 76.59; H, 8.73; N, 4.38.

EXAMPLE 40 4-(3'-Ethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol andits Hydrochloride

4-(3'-Ethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was preparedfrom 3-ethoxybromobenzene by the procedure described in Example 2; thefree base was converted to the hydrochloride salt which had a m.p. of229°-230° after crystallization from isopropyl alcohol. Anal. Calcd. forC₁₇ H₂₈ ClNO₂ : C, 65.05; H, 8.99; N, 4.46. Found: C, 65.19; H, 9.03; N,4.64.

EXAMPLE 414-(3'-Trifluoromethylphenyl)-α,α-dimethyl-1-ethyl-4-piperidinemethanol

4-(3'-Trifluoromethylphenyl)-α,α-dimethyl-1-ethyl-4-piperidinemethanolwas prepared as described in Example 2 except that 1-ethyl-4-piperidonewas used in place of 1-methyl-4-piperidone in the first step; m.p. 110°.Anal. Calcd. for C₁₇ H₂₄ F₃ NO: C, 64.74; H, 7.67; N, 4.44. Found: C,64.73; H, 7.90; N, 4.55.

EXAMPLE 42 4-(4'-Biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol

4-(4'-Biphenylyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from4-bromobiphenyl by the procedure described in Example 2; m.p. 192°-193°;NMR (in CDCl₃): τ2.2-2.8 (m, 9H); 7.1-8.5 (m+s, 12H) and 8.8 (s, 6H).

EXAMPLE 43 4-(3'-Methoxyphenyl)-α,α,1,3-tetramethyl-4-piperidinemethanol

4-(3'-Methoxyphenyl)-α,α,1,3-tetramethyl-4-piperidinemethanol wasprepared from 3-bromoanisole by the procedure of Example 2 except that1,3-dimethyl-4-piperidone was used in place of 1-methyl-4-piperidone inthe preparation of II. The product was obtained as an oil, distilling ata bath temperature of 130°-160° under 5×10⁻⁴ Torr (0.07 Pa) vacuum; itwas a mixture (ratio 83/17) of two isomers (R³ cis or trans to the arylgroup) as determined by 360 MHz NMR spectroscopy. The major isomer hasthe C-3 methyl group as a doublet (J=7.2 Hz) at τ 8.5 and the twoα-methyl groups at 8.7 and 8.9. MS Calcd. for C₁₇ H₂₇ NO₂ : m/z 277.204.Found: 277.204.

EXAMPLE 44 4-(3'-Tolyl)-α,α,1,2-tetramethyl-4-piperidinemethanol

4-(3'-Tolyl)-α,α,1,2-tetramethyl-4-piperidinemethanol was prepared from3-bromotoluene by the procedure of Example 2 except that1,2-dimethyl-4-piperidone was used in place of 1-methyl-4-piperidone inthe preparation of II; m.p. 139°; NMR (360 MHz in CDCl₃): τ 2.8-2.9 (m,3H); 3.0 (d, split further, 1H); 7.0 (m, 1H); 7.4 (m, 2H); 7.5-7.9(m+2s, 10H); 8.0 (broad s, 1H); 8.9 (two s, 6H) and 9.4 (d, J=7 Hz, 3H).Anal. Calcd. for C₁₇ H₂₇ NO: C, 78.11; H, 10.41; N, 5.36. Found: C,78.23; H, 10.31; N, 5.30.

EXAMPLE 457-(3'-Trifluoromethylphenyl)-α,α-dimethyl-7-indolizidinemethano

7-(3'-Trifluoromethylphenyl)-α,α-dimethylindolizidinemethanol wasprepared by the procedure of Example 2 except that 7-indolizidinone wasused in place of 1-methyl-4-piperidone in the preparation of II. Theproduct was a mixture of two stereoisomers in the ratio of 3:2, m.p.120°-122°. Anal. Calcd. for C₁₈ H₂₄ F₃ NO: C, 66.04; H, 7.39; N, 4.28.Found: C, 65.99; H, 7.48; N, 4.39.

EXAMPLE 46 (±)-cis andtrans-3-Methyl-1-[1'-methyl-4'-(3"-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanol

(±)-cis andtrans-3-Methyl-1-[1'-methyl-4'-(3"-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanolwas prepared, as a 60/40 mixture of the two racemic diastereomers, bythe procedure described in Example 2 except that(±)-3-methylcyclopentanone was used in place of acetone in thepreparation of III; m.p. 112°-113°. ¹⁹ F NMR spectrum; singlet at -62.6ppm (from Freon®11 CFCl₃); ¹ H-NMR spectrum: two doublets (J=7 Hz) at9.0 and 9.1 in the ratio of 2:3, among others.

EXAMPLE 47 (-)-cis andtrans-3-Methyl-1-[1'-methyl-4'-(3"-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanol

(-)-cis andtrans-3-Methyl-1-[1'-methyl-4'-(3"-trifluoromethylphenyl)-4'-piperidinyl]cyclopentanolwas prepared, as a mixture of two optically active diastereomers, by theprocedure described in Example 2 except that (-)-3-methylcyclopentanonewas used in the preparation of III; m.p. 103°-104°. [α]_(D) -6.7°(c=1.07, CHCl₃). The NMR spectra were identical to those of the productof Example 46.

DOSAGE FORMS

The antidepressant agents of this invention can be administered astreatment for psychiatric depressions of the reactive and endogenoustypes by any means that produces contact of the active agent with theagent's site of action in the body of a mammal. They can be administeredby any conventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butare generally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage administered will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the age, health andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; and the effectdesired. Usually, a daily dosage of active ingredient can be about 0.001to 50 milligrams per kilogram of body weight. Ordinarily, a total of0.01 to 20, preferably 0.1 to 10, milligrams per day per kilogram ofbody weight, given in divided doses 2 to 4 times a day or in sustainedrelease form, is effective to obtain the desired therapeutic results.

Dosage forms (compositions) suitable for internal administration cancontain about 0.25 to about 10 milligrams of active ingredient per unit.In such pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.01-90% by weight, based onthe total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets and powders, or in liquid dosage forms, suchas elixirs, syrups and suspensions; it can also be administeredparenterally, in sterile liquid dosage forms, or rectally in the form ofsuppositories.

Gelatin capsules can contain the active ingredient and powderedcarriers, such as lactose, sucrose, mannitol, starch, cellulosederivatives, magnesium stearate and stearic acid. Similar diluents canbe used to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or they can be enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose)and related sugar solutions and glycols, such as propylene glycol or thepolyethylene glycols, are suitable carriers for parenteral solutions.Solutions for parenteral administration contain preferably awater-soluble salt of the active ingredient, suitable stabilizing agentsand, if necessary, buffer substances. Antioxidizing agents, such assodium bisulfite, sodium sulfite and ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA (ethylenediaminetetraacetic acid). Inaddition, parenteral solutions can contain preservatives, such asbenzalkonium chloride, methyl- or propylparaben and chlorobutanol.

Suppositories can contain the active ingredient in a suitable oleaginousor water-soluble base. The oleaginous class includes cocoa butter andother fats with similar properties; the water-soluble class includes thepolyethylene glycols.

Suitable pharmaceutical carriers are described by E. W. Martin inRemington's Pharmaceutical Sciences, a standard reference text in thisfield.

Useful pharmaceutical dosage forms for administration of the compoundsof this invention are illustrated below.

CAPSULES (HARD)

Hard capsules can be prepared by filling standard two-piece hard gelatincapsules with the following mixture using conventional encapsulatingequipment:

Active ingredient: 1 mg

Lactose: 125 mg

Talc: 12 mg

Magnesium stearate: 3 mg

CAPSULES (Soft)

A mixture of active ingredient in soybean oil can be prepared andinjected by means of a positive displacement pump in gelatin to formsoft gelatin capsules containing 5 mg of the active ingredient. Thecapsules can be washed in petroleum ether and dried.

TABLETS

Tablets can be prepared by conventional procedures so that each unitwill contain:

Active ingredient: 1 mg

Spray dried lactose: 150 mg

Microcrystalline cellulose: 35 mg

Magnesium stearate: 3 mg

PARENTERAL

Parenteral composition suitable for intramuscular administration can beprepared so that each mL contains, percentages being by weight:

Active ingredient: 1 mg

Sodium carboxymethyl cellulose: 0.75%

Polysorbate 80: 0.04%

Benzyl alcohol: 0.9%

Sodium chloride: 0.9%

Water for injection Q.S.: 1 mL

SUSPENSION

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain, percentages being by weight:

Active ingredient: 5 mg

Methylcellulose: 5%

Carboxymethyl cellulose: 5%

Syrup: 30%

Polysorbate 80: 0.2%

Sodium saccharin: 2 mg

Cherry flavor: 0.1%

Sodium benzoate: 5 mg

Water Q.S.: 5 mL

USE

A standard procedure for detecting and comparing the antidepressantactivity of the compounds of this invention, for which there is goodcorrelation with human efficacy, is the prevention oftetrabenazine-induced sedation and depression in mice. (Everett, "TheDopa Response Potentiation Test and Its Use in Screening forAntidepressant Drugs", pp. 164-167 in Antidepressant Drugs [Proceedingsof the First International Symposium], S. Garattini and M. N. G. Dukes(editors), 1967).

Groups of 10 Carworth CF₁ S female mice, 18-21 g each, each fasted 1.5 hand were intubated with antagonist compounds at oral doses, such as 0,1, 3, 9, 27 and 81 mg/kg in 0.20 mL of 1% Methocel® (methylcellulose).The mice were challenged 30 minutes later with tetrabenazine (as themethanesulfonate), 32 mg/kg intraperitoneally (dissolved in 0.20 mL0.05% aqueous KCl at pH 2.0). One hour after administration ofantagonist (30 minutes after administration of tetrabenazine) the micewere examined for signs of exploratory activity and ptosis (eye lidclosure). Normal exploratory activity (relief from sedation) wasrecorded when a mouse, lifted by the tail from a group of 10 in atesting box and placed on a stainless steel testing box lid (12.5 inch(31.8 cm) by 8 inch (20.3 cm) with 0.33 inch mesh), either turned itshead horizontally 30° in both directions or moved to the edge of thescreen within 10 seconds after being placed on the screen. Relief fromptosis was recorded when, at exactly two seconds after placing the mousefacing the observer, lid closure was less than 50% in both eyes. Thefollowing table shows the data obtained from testing compounds of theaforesaid examples.

                  TABLE 2                                                         ______________________________________                                        ANTAGONISM OF TETRABENAZINE-INDUCED                                           DEPRESSION IN MICE ORALLY                                                     AT ONE HOUR POST-DRUG                                                                      ORAL ED.sub.50 (mg/kg)                                                        FOR PREVENTION OF                                                               EXPLORATORY                                                    EXAMPLE        LOSS          PTOSIS                                           ______________________________________                                         1                 5.6           0.78                                          2                 0.01          0.016                                           2A              0.01          0.014                                         3                 14.           2.8                                           4                 0.20          0.12                                          5                 0.48          0.33                                          6                 0.04          0.03                                          7                 0.57          0.33                                          8   (HCl Salt)    0.29          0.26                                          9                 0.48          0.33                                         10                 0.04          0.04                                         11                 0.69          0.57                                         12                 0.11          0.064                                        13                 0.30          0.23                                         14   (HCl Salt)    4.4           2.7                                          15                 2.3           0.57                                         16                 0.12*         0.077*                                       17                 0.10          0.11                                         18   (HCl Salt)    0.71          0.71                                         19                 1.1           0.33                                         20                 4.6           2.1                                          21                 1.3           1.3                                          22                 0.92          0.67                                         23                 38.           17.                                          24                 1.2           0.78                                         25                 0.99          0.69                                         26                 29.           18.                                          27                 1.4           0.9                                          28                 3.8           1.7                                          29                 0.99          0.86                                         30                 0.17          0.084                                        31   (HCl Salt)    0.064         0.056                                        32                 >81           81                                           33                 0.78          0.35                                         34                 0.48          0.45                                         35                 1.4           1.1                                          36   (HCl Salt)    1.1           0.66                                         37   (HCl Salt)    >81           81                                           38   (HCl Salt)    >81           >81                                          39                 0.33          <0.33                                        40   (HCl Salt)    0.9           0.9                                          41                 0.73          0.46                                         42                 1.5           1.0                                          43                 7.2           5.8                                          44                 0.33          0.33                                         45                 <0.33         0.48                                         46                 <1            <1                                           47                 <1            <1                                           Amtriptyline   2.7           0.7                                              (Standard)                                                                    Imipramine     2.2           0.94                                             (Standard)                                                                    ______________________________________                                         *peak time values                                                        

PROTOCOL FOR ANOREXIA DATA FROM CNS SCREEN

Female mice weighing 16-20 grams and fasted overnight for 17-21 h areused in these studies. At 0.5 h after administration of graded oraldoses of compound prepared in aqueous Methocel® (methylcellulose,viscosity 100 CPS, grade MC, Dow Chemical Co.) and 2.8% Tween 80 anddosed at 0.1 mL per 10 grams of body weight, each mouse is transferredto an individual, clear, Lucite® compartment (13.3 cm×12.7 cm×12.7 cm)with a 0.64 cm×0.64 cm wire mesh floor. Five compartments are linearlyarranged in each cage unit. Inside each compartment is a section of ablack Lucite® bar (13 cm×1.2 cm×1.2 cm), in the top of which are tenspot depressions (0.8 cm diameter), each containing 0.05 mL of 50%sweetened condensed milk (Borden's Eagle Brand). 30 Minutes later themice are returned to the "shoe-box" containers and the number of milkspots consumed by each mouse is counted. Fractions of spots consumed arealso estimated and counted. Five mice mg per drug dose can drink amaximum of 50 spots (2.5 mL of milk). Nine or fewer spots consumed by 5mice is considered to indicate anorexia. ED₅₀ values are estimated basedon the quantal responses obtained.

The data tabulated in Table 3 show that certain compounds of thisinvention have utility as anorectic agents, and thus may be useful intreating obesity.

                  TABLE 3                                                         ______________________________________                                        EXAMPLE     ED.sub.50 FOR ANOREXIA                                            ______________________________________                                         2          60           mg/kg                                                  2A        36                                                                 4          60                                                                 6          60                                                                 7          20                                                                 8          20                                                                10          20                                                                16          60                                                                17          60                                                                30          60                                                                31          20                                                                32          60                                                                37          60                                                                39          60                                                                41          60                                                                ______________________________________                                    

BEST MODE FOR CARRYING OUT THE INVENTION

The best mode presently contemplated for carrying out the invention isrepresented by the antidepressant of Example 2.

INDUSTRIAL APPLICABILITY

As is apparent from the description provided herein, the antidepressantsand anorectic agents of this invention are useful in the field ofmedicine, particularly in the areas of mental disorders and obesity.

Although the preferred embodiments of the invention have beenillustrated and described above, it is to be understood that it is notintended to limit the invention to the precise constructions disclosedherein and it is to be further understood that the right is reserved toall changes and modifications coming within the scope of the inventionas defined in the appended claims.

We claim:
 1. 4-Aryl-4-piperidinecarbinol of the formula: ##STR16##wherein (a) R¹ is H, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8carbon atoms or benzyl;(b) each of R² and R³ is independently selectedfrom H and lower alkyl of 1 to 4 carbon atoms; R¹ and R² taken togetheris a branched or unbranched alkylene bridge wherein the bridge is of 3or 4 carbon atoms; or R² and R³ taken together is a branched orunbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;(c) R⁴ is(1) phenyl or 2-naphthyl or phenyl or 2-naphthyl substitutedwith one or two substituents, the same or different, selected from F,Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio,perfluoroalkoxy, perfluoroalkylthio and dialkylamino, said alkyl andalkoxy moieties being of 1 to 12 carbon atoms and said aryl moietiesbeing of 6 to 12 carbon atoms; (2) 2-, 3-, or 4-biphenylyl or 2-, 3-, or4-biphenylyl wherein either or both aromatic moieties is substitutedwith one or two substituents, the same or different, selected from F,Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio,perfluoroalkoxy, perfluoroalkylthio and dialkylamino, said alkyl andalkoxy moieties being of 1 to 12 carbon atoms and said aryl moietiesbeing of 6 to 12 carbon atoms; (3) 2-pyrrolyl or 2-pyrrolyl substitutedwith one to three lower alkyl groups of 1 to 4 carbon atoms; (4) 2-, 3-,or 4-pyridyl; or (5) 2-thienyl substituted in the 5-position with loweralkyl of 1 to 4 carbon atoms; and (d) each of R⁵ and R⁶ is independentlyselected from alkyl of 1 to 12 carbon atoms and cycloalkyl of 3 to 8carbon atoms or R⁵ and R⁶ taken together is a branched or unbranchedalkylene bridge wherein the bridge is of 3 to 11 carbon atoms,provided,however, when R¹, R⁵ and R⁶ are methyl and R² and R³ are H, then R⁴ isnot p-t-butylphenyl or 2'-biphenylyl.
 2. 4-Aryl-4-piperidinecarbinol ofclaim 1 wherein R¹, R⁵ and R⁶ are methyl, R² and R³ are H and R⁴ ism--CF₃ C₆ H₄.
 3. Hydrochloride of the 4-aryl-4-piperidinecarbinol ofclaim
 2. 4. 4-Aryl-4-piperidinecarbinol of claim 1 wherein R⁴ is phenylwhich is m-substituted.
 5. 4-Aryl-4-piperidinecarbinol of claim 1wherein R¹ is benzyl.
 6. Pharmaceutical composition containing apharmaceutically effective antidepressive amount of the4-aryl-4-piperidinecarbinol of claim
 1. 7. Pharmaceutical compositioncontaining a pharmaceutically effective antidepressive amount of the4-aryl-4-piperidinecarbinol of claim
 2. 8. Pharmaceutical compositioncontaining a pharmaceutically effective antidepressive amount of thehydrochloride of claim
 3. 9. Pharmaceutical composition containing apharmaceutically effective antidepressive amount of the4-aryl-4-piperidinecarbinol of claim
 4. 10. Pharmaceutical compositioncontaining a pharmaceutically effective antidepressive amount of the4-aryl-4-piperidinecarbinol of claim
 5. 11. Method for treatingdepression, which method comprises administering a pharmaceuticallyeffective antidepressive amount of the 4-aryl-4-piperidinecarbinol ofclaim
 1. 12. Method for treating depression, which method comprisesadministering a pharmaceutically effective antidepressive amount of the4-aryl-4-piperidinecarbinol of claim
 2. 13. Method for treatingdepression, which method comprises administering a pharmaceuticallyeffective antidepressive amount of the hydrochloride of claim
 3. 14.Method for treating depression, which method comprises administering apharmaceutically effective antidepressive amount of the4-aryl-4-piperidinecarbinol of claim
 4. 15. Method for treatingdepression, which method comprises administering a pharmaceuticallyeffective antidepressive amount of the 4-aryl-4-piperidinecarbinol ofclaim 5.